Strained ring central nervous system depressants



United States Patent 3,429,912 STRAINED RING CENTRAL NERVOUS SYSTEM DEPRESSANTS Charles H. Jarboe and Robert Thomas Buckler, Louisville,

Ky., assignors to the United States of America as represented by the Secretary of the Department of Health, Education, and Welfare No Drawing. Filed Apr. 6, 1966, Ser. No. 540,491 U.S. Cl. 260468 6 Claims Int. Cl. 'C07c 125/06, 103/88; A61k 27/00 ABSTRACT OF THE DISCLOSURE Compounds such as N-acetyl cyclobutanecarboxamide; N-cyclobutyryl cyclobutanecarboxamide; N-butyryl cyclobutanecarboxamide; N-cyclobutyryl ethyl urethane; and 'y-cyclobutyryloxy-N-cyclobutyrybutyramide are found to be useful as anesthetics, sedatives, tranquilizers and anticonvulsants.

The present invention relates to central nervous system depressants and, more particularly, to amide derivatives of cyclobutanecarboxylic acid which are useful as anesthetics, sedatives, transquilizers and anti-convulsants.

The need for new and improved central nervous system (CNS) depressants continuously exists as certain specific and improved properties in various types of CNS depressants are desired. In addition, CNS depressants are needed having minimum deleterious side effects. Quick acting surgical anesthetics are also needed. Furthermore, the need for suitable anti-convulsants is particularly great since approximately 10-15% of all epileptics are not readily controlled with presently available anti-convulsants.

It is therefore an object of the present invention to overcome or alleviate problems existing in the prior art such as those indicated above.

It is another object of the present invention to provide new compounds having CNS depressant properties.

It is another object of the present invention to provide for an improved method for depressing of the central nervous system.

It is another object of the present invention to provide new and improved methods and compositions for depressing the central nervous system such as by providing improved anesthesia, sedation, tranquilizing and control of convlusions.

It is another object of the present invention to provide a quick acting anesthesia.

These and other objects and the nature and advantages of the present invention will be more apparent from the following detailed description.

In accordance with the present invention, new amide derivatives of cyclobutanecarboxylic acid have been discovered. It has also been discovered that these amide derivatives of cyclobutanecarboxylic acid have CNS depressant properties. In particular, it has been discovered that these compounds have the ability to anesthetize mammals almost instantly. The present properties are found to be highly dependent on the ring structure, since it has been found that the corresponding analogs of cyclopropanecarboxylic acid, cyclopentanecarboxylic acid, cyclopentylacetic acid and cyclohexanecarboxylic acid are inactive and do not function as CNS depressants.

In particular, the new amide derivatives of cyclobutanecarboxylic acid which have now been found to be elfective for the present purposes are N-acetyl cyclobutanecarboxamide; N-cyclobutyryl cyclobutanecarboxamide; N-butyryl cyclobutanecarboxamide; N-cyclobutyryl ethyl urethane; cyclobutanecarboxamide; and 'y-cyclobutyryloxy-N-cyclobutyrylbutyramide.

These compounds may be administered ina conventional manner along with conventional pharmaceutical carriers. For use as anesthesia, it has been found that a relatively high dosage is useful, the length of the period of anesthesia being dose dependent. Thus, the compounds may be administered intraperitoneally or intravenously as suspensions or solutions in 0.25% methyl cellulose solution in doses as high as 1000 milligrams per kilogram of mammal body weight. However, other pharmaceutical carriers may also be utilized and the materials may be administered in other manners.

Dosage amounts lower than 1000 mg./kg. will reduce the anesthetic effect (i.e., reduce the average sleeping time). Small dosage amounts are useful as sedatives, tranquilizers and anti-convulsants.

A substantial advantage of the above compounds, particularly when used in large dosage amounts to effect anesthesia, is that the animals treated are almost instantly anesthetized. Dosage units as low as 300 mg./kg. cause loss of righting reflex in only 30-60 seconds and lower dosages produce a marked lowering of spontaneous activity.

In addition, the compounds seem to lack any toxicity or other observable deleterious side eifects during testing on animals. Similar derivitives of cycloprop-anecarboxylic acid on the other hand, have LD values of only 250- 350 mg. per kg. In addition, the present compounds do not activate enzyme systems promoting their own metabolic degradation.

The following examples are illustrative of the invention, but are not to be considered as limiting thereof:

Example 1.N-acety1 cyclobutanecarboxamide A solution containing 14 grams (0.14 mole) of cyclobutanecarbonamide, 11 ml. '(0.=15 mole) of acetic anhydride and 2.5 ml. (0.03 mole) of 'acetyl chloride was refluxed for 40 minutes and was then poured, with stirring, into 100 g. of crushed ice. The resulting solution was neutralized with a 5% solution of sodium bicarbonate and was then extracted three times with 1'50 ml. fractions of diethyl ether. The solvent was evaporated to yield 11 g. of N-acetyl cyclobut-anecarboxamide, melting point 79-84 C. The material was purified by crystallization from n-pentane giving fine white needles having a melting point of 88 C.

Calculated for C H O N: C, 59.56 and H, 7.85. Found: C, 59.75 and H, 8.04.

The N-acetyl cyclobutanecarboxamide was put into 0.25% methyl cellulose solution. The solution was injected into a series of mice in dosage units from 100 mg. per kg. to 1,000 mg. per kg. The CNS depressant effects were noted in 30-60 seconds. The average sleeping time for 1,000 mg. per kg. was 6.5 hours and no deaths or observable side effects ensued. Small dosage amounts provided the properties of sedation, apparent tranquilization and further appeared to be useful as anti-convulsants.

Example 2.N-cyclobutyryl cyclobutanecarboxamide A solution containing 3 g. (0.03 mole) of cyclobutanecarboxamide and 5 ml. of pyridine, which had been previ ously washed with neutral alumina and dried over potassium hydroxide, was mixed with 3.6 g. (0.03 mole) of cyclobutanecarbonyl chloride which was added dropwise. An exothermic reaction ensued and the mixture heated on a steam bath for one hour. At the end of this time the resulting clear brown solution was poured with stirring into 100 g. crushed ice. The product separated as a flocculent white powder to yield 4.1 g. of N-cyclobutyryl cyclobutanecarboxamide having a melting point of 167-l69 C. This was purified by crystallization from distilled water after treatment of the solution with charcoal 3 to provide plates having silver-white color and a melting point of 173 C.

Calculated for C H O N: C, 66.27 and H, 8.34. Found: C, 66.43 and H, 8.43.

As in Example 1, the compound, i.e., N-cyclobutyryl cyclobutanecarboxamide, was administered intra-peritoneally into mice as suspensions or solutions in 0.25% methyl cellulose solution in doses ranging from 100-1000 mg. per kg. The effects were noted in 30-60 seconds. At high concentrations, the compound acted as a long term surgical anesthesia, the average sleeping time for a 1,000 mg. per kg. dosage being 7.6 hours. Even at the high dosage, no deaths or other evidence of toxicity resulted and there was no evidence of observable side effects.

Example 3.N-butyryl cyclobutanecarboxamide A solution containing 0.75 g. (0.009 mole) of butyramide was made with 5 ml. of pyridine which had been washed with neutral alumina and dried over potassium hydroxide. l g. (0.009 mole) of cyclobutanecarbonyl chloride was then added dropwise to the solution. An exothermic reaction ensued and the mixture heated on a steam bath for one hour. At the end of this time the dark brown solution Was poured into 100 g. crushed ice. The product separated as a light tan precipitate to yield 0.92 g. (60%) of N-butyryl cyclobutanecarboxamide having a melting point of 130 C. Crystallization from n-hexane gave fine white needles having a melting point of 139 C.

Calculated for C H O N: C, 63.88 and H, 8.94. Found: C, 64.17 and H, 8.95.

The resultant N-butyryl cyclobutanecarboxamide was administered to a series of mice intra-peritoneally as in Examples 1 and 2. The effects were noted in 30-60 seconds. The average sleeping time for a 1,000 mg. per kg. dosage was 7.9 hours. There was no evidence of toxicity and no observable side effects.

Example 4.N-cyclobutyryl ethyl urethane A solution was formed of 0.8 g. (0.009 mole) of ethyl urethane and ml. of pyridine which had been prewashed with neutral alumina and dried over potassium hydroxide. To this solution 1 g. (0.009 mole) of cyclobutane carbonyl chloride was added dropwise. The mixture was heated for one hour on a steam bath and at the end of this time was poured into 100 g. of crushed ice. The product slowly separated as a buff-colored, semi-crystalline powder to yield 0.8 g. (53%) of the N-cyclobutyryl ethyl urethane having a melting point of 80 C. Crystallization from n-hexane gave fine white needles having a melting point of 83 C.

The urethane was utilized in accordance with the procedures of Examples 1 and 2. The effects were noted in 30-60 seconds. The average sleeping time for a 1,000 mg. per kg. dosage in mice was 5 hours. Once again, no toxicity resulted and no other side eitects were observed.

Example 5.-'y-Cyclobutyryloxy-N- cyclobutyrylbutyramide A solution was made from 0.89 g., 0.01 mole, 'y-hydroxybutyramide and 5 ml. of neutral alumina washed pyridine. The solution was cooled on an ice bath and 2.04 g., 0.02 mole, of cyclobutanecarbonyl chloride added dropwise with stirring. An exothermic reaction ensued. When the mixture had cooled to approximately 30 C. it was placed on a steam bath and heated for one hour. At the end of this time the brown solution was poured into 100 g. of crushed ice. The product separated as a light tan precipitate to yield 0.6 g. (22%) of 'y-cyclobutyryloxy-N-cyclobutyrylbutyramide, M.P. 80 C. Crystallization from nheptane gave white plates, M.P. 90 C.

Calculated for C H O N: C, 62.90 and H, 7.92. Found: C, 62.80 and H, 7.89.

The 7 cyclobutyryloxy-N-cyclobutyrylbutyramide was put into 0.25 methyl cellulose solution. It was injected into a series of mice in dosage units from mg. per kg. to 1,000 mg. per kg. The effects were noted in 30-60 seconds. The average sleeping time for 1,000 mg. per kg. was 13 hours and no deaths or observable side eifects were observed. Small doses provided sedation and loss of spontaneous activity.

Example 6.Cyclobutanecarboxamide cyclobutanecarboxamide, a known compound, was administered to mice intra-peritoneally as suspensions or solution in 0.25% methyl cellulose solution in dosages ranging from 100-1000 ml. per kl. of mouse body weight as in Examples 1 and 2. Even at the high dosage rate, no toxicity or other side efiects were observed. The average sleeping time for 1,000 mg. per kg. was 11.6 hours. Loss of spontaneous activity, by comparison with the other compounds, was very slow in developing, e.g., at 500 mg./ kg. the loss of spontaneous activity took ten minutes to develop.

Mice were selected as the test animals since they are, in general, somewhat insensitive to various classes of CNS depressants. The above examples, therefore, constitute a relatively rigorous test. The above compounds were used as general anesthetics for surgery. They are characterized by smooth induction and rapid attainment of surgical plane anesthesia. Of particular advantage in the above compounds is their apparently complete lack of any deleterious side effects even at very high dosage levels. There were no requirements for trachectomy, use of curaremimetics or atropine to reduce secretion and no cardiac or blood pressure efiects.

As with many CNS depressants, the effect produced by the compounds is dose dependent, high dosage levels providing anesthesia and lower levels providing sedation, tranquilization and anti-convulsion properties.

It will be obvious to those skilled in the art that various changes may be made without departing from the spirit of the invention and therefore the invention is not limited to what is described but only as indicated in the appended claims.

What is claimed is:

1. A compound selected from the group consisting of N-acetyl cyclobutanecarboxamide; N-cyclobutyryl cyclobutanecarboxamide; N-butyryl cyclobutanecarboxamide; N-cyclobutyryl ethyl urethane; and -cyclobutyryloxy-N cyclobutyrylbutyramide.

2. N-acetyl cyclobutanecarboxamide.

3. N-cyclobutyrylcyclobutanecarboxamide.

4. 'y-butyryl cyclobutanecarboxamide.

5. N-cyclobutyryl ethyl urethane.

6. 'y-Cyclobutyryloxy-N-cyclobutyrylbutyramide.

References Cited Wagner and Zook: Synthetic Organic Chemistry, I. Wiley & Sons, New York 1953 p. 576.

P. Dunn et a1. Recuel des Travaux Chimiques des Pays- Bas, T. 71 1952.

LORRAINE A. WEINBERGER, Primary Examiner. PAUL J. KILLOS, Assistant Examiner.

U.S. Cl. X.R. 

